TY - JOUR
T1 - Age-associated increase in salt sensitivity is accompanied by a shift in the atrial natriuretic peptide modulation of the effect of marinobufagenin on renal and vascular sodium pump
AU - Fedorova, Olga V.
AU - Kashkin, Vladimir A.
AU - Zakharova, Irina O.
AU - Lakatta, Edward G.
AU - Bagrov, Alexei Y.
PY - 2012/9
Y1 - 2012/9
N2 - Background: Marinobufagenin (MBG) promotes natriuresis via inhibition of renotubular Na/K-ATPase (NKA) and causes vasoconstriction via inhibition of vascular NKA. Atrial natriuretic peptide (ANP), via cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-dependent mechanism, sensitizes renal NKA to MBG but reduces MBG-induced inhibition of vascular NKA. As aging is associated with a downregulation of cGMP/PKG signaling, we hypothesized that in older rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG. Methods: In younger (3-month-old) and older (12-month-old) Sprague-Dawley rats, we compared SBP, natriuresis, activity of NKA in aorta and renal medulla, and levels of MBG and α-ANP at baseline and following acute NaCl loading (20%, 2.5ml/kg, intraperitoneally), and studied modulation of MBG-induced NKA inhibition by α-ANP in vitro. Results: As compared with younger rats, NaCl-loaded older rats exhibited a greater MBG response, greater SBP elevation (25 vs. 10mmHg, P<0.01) and greater inhibition of NKA in aorta (39 vs. 7%, P<0.01), 30% less natriuresis, and less inhibition of renal NKA (25 vs. 42%, P<0.05) in the presence of comparable responses of α-ANP and cGMP. In aorta and kidney of older rats, the levels of PKG were reduced, the levels of phosphodiesterase-5 were increased compared with that in young rats, and α-ANP failed to modulate MBG-induced NKA inhibition. Conclusion: Age-associated downregulation of cGMP/PKG-dependent signaling impairs the ability of ANP to modulate the effects of MBG on the sodium pump, which contributes to salt sensitivity.
AB - Background: Marinobufagenin (MBG) promotes natriuresis via inhibition of renotubular Na/K-ATPase (NKA) and causes vasoconstriction via inhibition of vascular NKA. Atrial natriuretic peptide (ANP), via cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-dependent mechanism, sensitizes renal NKA to MBG but reduces MBG-induced inhibition of vascular NKA. As aging is associated with a downregulation of cGMP/PKG signaling, we hypothesized that in older rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG. Methods: In younger (3-month-old) and older (12-month-old) Sprague-Dawley rats, we compared SBP, natriuresis, activity of NKA in aorta and renal medulla, and levels of MBG and α-ANP at baseline and following acute NaCl loading (20%, 2.5ml/kg, intraperitoneally), and studied modulation of MBG-induced NKA inhibition by α-ANP in vitro. Results: As compared with younger rats, NaCl-loaded older rats exhibited a greater MBG response, greater SBP elevation (25 vs. 10mmHg, P<0.01) and greater inhibition of NKA in aorta (39 vs. 7%, P<0.01), 30% less natriuresis, and less inhibition of renal NKA (25 vs. 42%, P<0.05) in the presence of comparable responses of α-ANP and cGMP. In aorta and kidney of older rats, the levels of PKG were reduced, the levels of phosphodiesterase-5 were increased compared with that in young rats, and α-ANP failed to modulate MBG-induced NKA inhibition. Conclusion: Age-associated downregulation of cGMP/PKG-dependent signaling impairs the ability of ANP to modulate the effects of MBG on the sodium pump, which contributes to salt sensitivity.
KW - Na/K-ATPase
KW - aging
KW - cyclic guanosine monophosphate
KW - dietary sodium
KW - hypertension
KW - marinobufagenin
KW - natriuretic peptides
KW - protein kinase G
KW - salt sensitivity
UR - http://www.scopus.com/inward/record.url?scp=84865501660&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865501660&partnerID=8YFLogxK
U2 - 10.1097/HJH.0b013e328356399b
DO - 10.1097/HJH.0b013e328356399b
M3 - Article
C2 - 22796708
AN - SCOPUS:84865501660
SN - 0263-6352
VL - 30
SP - 1817
EP - 1826
JO - Journal of hypertension
JF - Journal of hypertension
IS - 9
ER -